The development of organ-conserving treatment for locally advanced head and neck cancers shifted the paradigm for treatment. A decade ago, we developed the strategy of selecting patients for chemoradiotherapy or for laryngectomy based on their response to a single cycle of chemotherapy. This approach results in 3-year cause-specific survival and laryngeal preservation rates of 87% and 70%, respectively. However, chemoradiation is associated with an increased rate of mucositis and dysphagia compared with radiotherapy alone. The long-term goal of this application is to preserve a high rate of larynx preservation while decreasing the toxicity of treatment by using cetuximab-radiation instead of chemoradiotherapy in patients selected to benefit from this approach. These goals will be achieved through 3 specific aims. Specific Aim 1 is to decrease the toxicity of larynx-preserving treatment by using cetuximab-radiation in place of chemoradiation in appropriately selected patients. In Aim 1A we propose to extend our current strategy in a phase II study of cetuximab-radiation for patients who would previously have received chemoradiation: those responding to a cycle of chemotherapy. In Aim 1B, we propose to assess tumor biopsies in the patients who respond to a cycle of chemotherapy and then receive cetuximab for markers of EGFR activation and downstream inhibition as possible predictors of response to cetuximab-radiation. Specific Aim 2 is to investigate the potential of established markers (Aim 2A) and to discover potential new biomarkers (Aim 2B) by assessment of phosphoproteome to predict response to cetuximab combined with radiation. Our preliminary data suggest that the extent and duration of decrease in the established markers like total EGFR, pEGFR, pSTATS, Bcl-XL, and Ki67 correlate with response to the combination of EGFR inhibitors and radiation. In this aim, we propose to extend these studies to a total of 20 head and neck xenografts, 10 responsive and 10 non-responsive. In Aim 2B we will assess the effects of cetuximab-radiation on phosphoproteins using proteomic technology. Our preliminary data indicate that this is a promising method of identifying novel phosphoproteins that are affected by cetuximab treatment. Specific Aim 3 is to carry out preclinical studies to improve the efficacy of EGFR inhibition with radiochemotherapy. In Aim 3A, we focus on the potential importance of schedule for combining EGFR inhibition with radiochemotherapy. In Aim 3B we will focus on a novel approach toward targeting EGFR via HSP90 inhibition. Our preliminary data show that geldanamycin, an inhibitor of HSP90, accelerates the degradation of EGFR in cisplatin resistant cells, leading to both cellular toxicity and radiosensitization. We feel our preclinical and clinical team with an extensive track record in this field makes it likely that these studies will improve patient outcome.